Dataset Information

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5.

ABSTRACT: Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa. Methods: Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839). Results: We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab. Conclusion: This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine.

SUBMITTER: Giuliano S

PROVIDER: S-EPMC6401402 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5.

Giuliano Sandy S Dufies Maeva M Ndiaye Papa Diogop PD Viotti Julien J Borchiellini Delphine D Parola Julien J Vial Valérie V Cormerais Yann Y Ohanna Mickaël M Imbert Véronique V Chamorey Emmanuel E Rioux-Leclercq Nathalie N Savina Ariel A Ferrero Jean-Marc JM Mograbi Baharia B Pagès Gilles G

Theranostics 20190130 4

Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We ...[more]

PMID: 30867824

Similar Datasets

Project description:Transcription factor EB (TFEB) is a master transcriptional regulator playing a key role in lysosomal biogenesis, autophagy and lysosomal exocytosis. TFEB activity is inhibited following its phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) on the surface of the lysosome. Phosphorylated TFEB is bound by 14-3-3 proteins, resulting in its cytoplasmic retention in an inactive state. It was suggested that the calcium-dependent phosphatase calcineurin is responsible for dephosphorylation and subsequent activation of TFEB under conditions of lysosomal stress. We have recently demonstrated that TFEB is activated following exposure of cancer cells to lysosomotropic anticancer drugs, resulting in lysosome-mediated cancer drug resistance via increased lysosomal biogenesis, lysosomal drug sequestration, and drug extrusion through lysosomal exocytosis. Herein, we studied the molecular mechanism underlying lysosomotropic-drug-induced activation of TFEB. We demonstrate that accumulation of lysosomotropic drugs results in membrane fluidization of lysosome-like liposomes, which is strictly dependent on the acidity of the liposomal lumen. Lysosomal accumulation of lysosomotropic drugs and the consequent fluidization of the lysosomal membrane, facilitated the dissociation of mTOR from the lysosomal membrane and inhibited the kinase activity of mTORC1, which is necessary and sufficient for the rapid translocation of TFEB to the nucleus. We further show that while lysosomotropic drug sequestration induces Ca2+ release into the cytoplasm, facilitating calcineurin activation, chelation of cytosolic Ca2+, or direct inhibition of calcineurin activity, do not interfere with drug-induced nuclear translocation of TFEB. We thus suggest that lysosomotropic drug-induced activation of TFEB is mediated by mTORC1 inhibition due to lysosomal membrane fluidization and not by calcineurin activation. We further postulate that apart from calcineurin, other constitutively active phosphatase(s) partake in TFEB dephosphorylation and consequent activation. Moreover, a rapid export of TFEB from the nucleus to the cytosol occurs upon relief of mTORC1 inhibition, suggesting that dephosphorylated TFEB constantly travels between the nucleus and the cytosol, acting as a rapidly responding sensor of mTORC1 activity.

Project description:BACKGROUND: Schizophrenia and bipolar disorder (BD) are psychiatric diseases that are commonly managed with antipsychotics. Treatment pathways are highly variable and no universal treatment guidelines are available. The primary objective of the Italian Burden of Illness in Schizophrenia and BD (IBIS) study was to describe pharmaco-utilisation of antipsychotic treatments and characteristics of patients affected by schizophrenia or BD. A secondary objective was to describe costs of illness for patients with schizophrenia or BD. METHODS: IBIS was a multicentre, real-world, retrospective, observational cohort study based on data obtained from administrative databases of 16 Local Health Units in Italy (~7.5 million individuals). Patients with schizophrenia or BD ?18 years of age treated with antipsychotics between 1 January 2008 and 31 December 2009 were included in the primary analysis. Pharmaco-utilisation data were gathered over a follow-up period of 12 months. RESULTS: Patients with schizophrenia and BD received a wide variety of antipsychotic medications. The proportion of patients on antipsychotic monotherapy was 68% in patients with schizophrenia and 70% in patients with BD. In patients with schizophrenia, ~1/3 of patients receiving antipsychotic monotherapy also received mood stabilisers and/or antidepressants (34.7%) compared with over half of those on antipsychotic polytherapy (52.2%). In patients with BD, use of mood stabilisers and/or antidepressants was even higher; 76.9% of patients receiving antipsychotic monotherapy also received mood stabilisers and/or antidepressants compared with 85.5% of patients on antipsychotic polytherapy. Switch therapy was more frequent in patients with BD than in patients with schizophrenia, whereas add-on therapy was more frequent in patients with schizophrenia than in patients with BD. The mean total disease-related cost per patient per annum was higher in patients with schizophrenia (€4,157) than in patients with BD (€3,301). The number and cost of hospitalisations was higher in patients with BD, whereas the number and cost of nursing home stays was higher in patients with schizophrenia. CONCLUSION: Use of administrative databases has permitted retrieval of comprehensive information about therapeutic pathways, diagnostic history and costs in patients affected by schizophrenia or BD. A need for personalised treatment pathways has been described. TRIAL REGISTRATION: clinicaltrials.gov: NCT01392482 ; first received June 29, 2011.

Project description:This is the first study to assess human health risks due to the exposure of 'repurposed' pharmaceutical drugs used to treat Covid-19 infection. The study used a six-step approach to determine health risk estimates. For this, consumption of pharmaceuticals under normal circumstances and in Covid-19 infection was compiled to calculate the predicted environmental concentrations (PECs) in river water and in fishes. Risk estimates of pharmaceutical drugs were evaluated for adults as they are most affected by Covid-19 pandemic. Acceptable daily intakes (ADIs) are estimated using the no-observed-adverse-effect-level (NOAEL) or no observable effect level (NOEL) values in rats. The estimated ADI values are then used to calculate predicted no-effect concentrations (PNECs) for three different exposure routes (i) through the accidental ingestion of contaminated surface water during recreational activities only, (ii) through fish consumption only, and (iii) through combined accidental ingestion of contaminated surface water during recreational activities and fish consumption. Higher risk values (hazard quotient, HQ: 337.68, maximum; 11.83, minimum) were obtained for the combined ingestion of contaminated water during recreational activities and fish consumption exposure under the assumptions used in this study indicating possible effects to human health. Amongst the pharmaceutical drugs, ritonavir emerged as main drug, and is expected to pose adverse effects on r human health through fish consumption. Mixture toxicity analysis showed major risk effects of exposure of pharmaceutical drugs (interaction-based hazard index, HIint: from 295.42 (for lopinavir + ritonavir) to 1.20 for chloroquine + rapamycin) demonstrating possible risks due to the co-existence of pharmaceutical in water. The presence of background contaminants in contaminated water does not show any influence on the observed risk estimates as indicated by low HQadd values (<1). Regular monitoring of pharmaceutical drugs in aquatic environment needs to be carried out to reduce the adverse effects of pharmaceutical drugs on human health.

Dataset Information

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5.

Publications

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets